Genetic Variant CHRNA3:c.*163dupA (chr15-78596440-A-AT) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_000743.5(CHRNA3):c.*163dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0073 ( 2 hom. )

Consequence

CHRNA3
NM_000743.5 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.998

Publications

2 publications found

Variant links:

Genes affected

CHRNA3 (HGNC:1957): (cholinergic receptor nicotinic alpha 3 subunit) This locus encodes a member of the nicotinic acetylcholine receptor family of proteins. Members of this family of proteins form pentameric complexes comprised of both alpha and beta subunits. This locus encodes an alpha-type subunit, as it contains characteristic adjacent cysteine residues. The encoded protein is a ligand-gated ion channel that likely plays a role in neurotransmission. Polymorphisms in this gene have been associated with an increased risk of smoking initiation and an increased susceptibility to lung cancer. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2009]

CHRNA3 Gene-Disease associations (from GenCC):

urinary bladder, atony of
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, G2P

CHRNA3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000873 (131/149986) while in subpopulation NFE AF = 0.00104 (70/67270). AF 95% confidence interval is 0.000844. There are 0 homozygotes in GnomAd4. There are 59 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000743.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CHRNA3	NM_000743.5	MANE Select	c.*163dupA	3_prime_UTR	Exon 6 of 6	NP_000734.2
CHRNA3	NM_001166694.2		c.1390-3250dupA	intron	N/A	NP_001160166.1	P32297-3
CHRNA3	NR_046313.2		n.1784+99dupA	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CHRNA3	ENST00000326828.6	TSL:1 MANE Select	c.*163dupA	3_prime_UTR	Exon 6 of 6	ENSP00000315602.5	P32297-2
CHRNA3	ENST00000348639.7	TSL:1	c.1390-3250dupA	intron	N/A	ENSP00000267951.4	P32297-3
CHRNA3	ENST00000559002.5	TSL:1	n.193+99dupA	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000874

AC:

131

AN:

149880

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000880

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000664

Gnomad ASJ

AF:

0.000581

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000841

Gnomad FIN

AF:

0.000200

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00104

Gnomad OTH

AF:

0.00243

GnomAD4 exome

AF:

0.00727

AC:

6872

AN:

944894

Hom.:

Cov.:

AF XY:

0.00742

AC XY:

3338

AN XY:

449906

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00422

AC:

AN:

21336

American (AMR)

AF:

0.00707

AC:

AN:

9192

Ashkenazi Jewish (ASJ)

AF:

0.0117

AC:

149

AN:

12778

East Asian (EAS)

AF:

0.00245

AC:

AN:

20858

South Asian (SAS)

AF:

0.00727

AC:

207

AN:

28462

European-Finnish (FIN)

AF:

0.0142

AC:

290

AN:

20388

Middle Eastern (MID)

AF:

0.0114

AC:

AN:

2628

European-Non Finnish (NFE)

AF:

0.00715

AC:

5647

AN:

790216

Other (OTH)

AF:

0.00879

AC:

343

AN:

39036

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.279

Heterozygous variant carriers

836

1671

2507

3342

4178

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

162

324

486

648

810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000873

AC:

131

AN:

149986

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

73198

show subpopulations

African (AFR)

AF:

0.000878

AC:

AN:

41018

American (AMR)

AF:

0.000663

AC:

AN:

15082

Ashkenazi Jewish (ASJ)

AF:

0.000581

AC:

AN:

3444

East Asian (EAS)

AF:

0.000195

AC:

AN:

5134

South Asian (SAS)

AF:

0.000842

AC:

AN:

4752

European-Finnish (FIN)

AF:

0.000200

AC:

AN:

10008

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00104

AC:

AN:

67270

Other (OTH)

AF:

0.00240

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

256

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over